DESCRIPTION: (Applicant's Abstract) The development of invasive cancer involves changes in cell adhesion which allow transformed cells to invade and migrate through their underlying extracellular matrix. The applicant's laboratory has identified the human form of a tyrosine kinase, called the focal adhesion kinase (FAK), which is thought to transduce signals at points where cells contact the extracellular matrix, and have shown that p125fak is overexpressed as epithelial and mesenchymal cells become invasive. The applicant's preliminary data have shown that when FAK is attenuated by antisense oligonucleotide treatment in tumor cells, cell adhesion is disrupted and apoptosis is induced. This forms a conceptual framework of cell/ extracellular matrix interactions, signaling, and growth control, upon which the applicant's hypothesis that FAK is involved in the development of invasive cancer and could be a target for gene-directed therapeutics is based. This application focuses on the biology of FAK in the development of invasive cancer and the role of specific anti-FAK therapeutics to induce apoptosis in human tumor systems. To test this hypothesis, the clinical correlation between the level of p125fak expression, the components of its signaling pathway, and the invasive potential of a human tumor will be determined in defined data sets of breast and colon cancers. Using these clinical observations and his FAC cDNA constructs, he will define the biological mechanisms by overexpressing FAK, the components of its signaling pathway, and a dominant-negative protein in tumor cells and test the effects on tumor invasion and metastasis. He will then use his metastatic model systems to define the biological effects of attenuating FAK expression in vivo, using antisense oligonucleotides and adenovirus-mediated gene delivery systems. Thus, once the biological significance of FAK in tumor invasion is defined, and methods perfected to attenuate its signaling function, a directly translatable method of novel therapeutics to human malignancies will be accomplished.